The present study was undertaken to develop an optimum immunosuppressive regimen in baboon-to-monkey life-supporting kidney xenografts. Baseline therapy for all groups include cyclosporine (CsA) and steroids. We compared adding (1) cyclophosphamide (CyP) at dose of 20 mg/kg/day given on post-operative day (POD) 0, 2, 5 and 7; (2) mycophenolic mofetil (MMF) at a dose of 40 mg/kg/day by daily gavage; or (3) CyP + rapamycin (Rap). The latter group was divided into high and low dose subgroups. Untreated xenografts were rejected on POD 6, CsA alone treated xenografts survived for 35 days and CsA + CyP treated xenografts survived for 45 days. Adding MMF significantly prolonged mean survival to 111 ± 53 days, but the xenografts eventually developed rejection. Combination therapy including CsA, CyP and Rap reliably prevented xenogenic rejection and achieved a mean survival of 290 ± 30 days. However, high dose CyP + Rap led to high incidence of post-transplant lymphoproliferation disorders (PTLD), while the incidence of PTLD was significantly less in the low dose subgroup (P < 0.01). Four animals in this subgroup survived for more than 300 days with normal renal function and histology. In addition, two liver recipients treated with CsA + CyP survived for 91 and 1076 days. We conclude that long-term survival of kidney or liver xenografts can be achieved in a non-human concordant xenograft model using currently available immunosuppressive agents.
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